1. Field of the Invention
The present invention relates to the use of chemical compounds in medicine, more specifically, to the use of the compounds selected from hydrogenated pyrido[4,3-b]indoles for the treatment of neurodegenerative diseases, and especially Alzheimer's disease (AD), due to the discovery of new properties intrinsic to these compounds.
2. Description of the Related Art
Alzheimer's disease is currently one of the severest and widely spread neurodegenerative diseases. The most traditional approach to the treatment of this disease is compensatory therapy based on the compensation of the cholinergic system functions which are reduced in Alzheimer's disease. One of the therapeutic agents used in the alleged method of treatment is tacrine hydrochloride (hereinafter referred to as tacrine) which is 9-amino-1,2,3,4-tetrahydroacridine hydrochloride represented by the formula (A): ##STR2##
The mechanism of action of the said agent involves inhibiting choline esterase (Volger B. W. "Alternatives in the treatment of memory loss in patient with Alzheimer's disease. (Clinical Pharmacy. Jun. 10 , 1991 (6): 447-56). As for the choline esterase inhibiting activity, tacrine is an analogue of the world famous physostigmine and is a traditional anticholine esterase agent. However, the treatment with tacrine is not always effective. Besides, tacrine tends to cause undesirable side-effects.
A wide range of neurological diseases such as Alzheimer's disease, Huntington chorea, amiotrophic lateral sclerosis as well as brain ischemia are known to be associated with an excitotoxic effect of neuromediatory excitatory amino acids (EAA) such as glutamate and aspartate (Excitatory Amino Acids and Drug Research, Ed. by M. R. Szewczak N. I. Hrib Alan R. Liss, Inc., New York, 1989, p.380; The NMDA Receptor. Eds. Watkins & Collingridge G., 1989, IRL Press). In accordance with this mechanism, hyperexcitation of neurones in prolonged activation of their N-methyl-D-aspartate (NMDA) receptors with glutamate results in an excessive entry of potassium ions into the cell which initiates a number of pathological metabolic processes finally causing the death of nerve cells (Mattson, Neurone, 1990, v.2, p.105, Mill S. Kater, Neuron, 1990, v.2, p.149; Saitch et al, Lab Suvest. 1991, v.64, p.596).
More specifically in Alzheimer's disease, death of numerous neurones is believed to occur as follows. An endogenic oligopeptide, such as .beta.-amyloid, is a neurotoxic factor inducing neurodegenerative processes in the neurones. .beta.-Amyloid is present in the neurotic plaques abundantly located on the surface of the brain of the patients suffering from Alzheimer's disease (Prelli et al., --J. Neurochem., 1988, v.51, p.648; Yanuer et al., --Science, 1990, v.250, p.279). As shown by the investigations of recent years, .beta.-amyloid significantly enhances the excitotoxic effect of glutamate which is effected through the NMDA-receptor system (Koh et al., Brain Res., 1990, v.533, p.315; Mattson et al., --J. Neurosci., 1992, v. 12, p.376). As a result, the glutamate mediator at concentrations that are nontoxic under normal conditions becomes toxic for neurones under conditions of the developing .beta.-amyloid dose and causes their death.
In this connection, the search for effective antagonists of the brain NMDA-receptors capable of preventing the realization of the neurotoxic effect of EAA appears to be an original and promising approach to creation of neuroprotectors of a wide spectrum of activity including agents which can prevent the development of Alzheimer's disease and be useful for treatment of such diseases as Alzheimer's disease (Maragos W. F. et al., Trends Neurosci.,1987, No. 10, p.65).
A well known NMDA receptor antagonist is 2-amino-5-phosphonovaleric acid (AP5) (Evans et al., --Brit. J. Pharmacol., 1982, v.75, p.65). The main disadvantage of AP5 compound a side neurotoxic effect (such as the disturbance of coordination of movement and a sedative effect) which becomes apparent when AP5 is used in the doses in which it produces anti-NMDA effect (ED.sub.50 =190 mg/kg) (Grigoriev et al. Chim. Pharm. Journal, 1988, No.3, p. 275-277). An intensive search for and trials of the agents having the anti-NMDA properties but without the neurotoxic effects is currently under way for treatment of the neurodegenerative diseases. However, to date such agents have not been available in clinics.